Synthesis of vitamin a



Patented Feb. 13, 1945 SYNTHESIS OF VITAMIN A Nicholas A. Milan, Belmont, Mala, assignor to Research Corporation, New York, N. Y., a cor- Duration of New York No Drawing. Application March 3, 1942, Serial No. 433,234

Claims.

The object at the present invention is to pro.- vide a new method for the synthesis of vitamin A and this invention constitutes a continuation-inpart 01 my co-pending applications Serial No. 353,775, filed August 22, 1940, and Serial No. 433,226, filed March 3, 1942.

The first essential step in the synthesis conslots in allowing the Grignard (Compound I) or the Grignard (Compound Ia) in which X stands for halogen (Compounds I and Ia are disclosed as the Grignards of Compounds V and Va in my application Serial No. 433,226, filed March 3, 1942) to react in an atmosphere of nitrogen with Compound II in which R may be either an alkyl or an aryl group such as methyl, phenyl, palmityl, etc. to form Compound III or Compound IIla.

CHI

HE C:

Cbmpouad I H1O Compound H Compound Io HlC OH:

OH: H H

Ell

Compound I" in the presence of active iron, the actylene bond is partially hydrogenated to an ethylene bondthereby forming Compound IV or Compound No.

me on; cni

I l 1': n H H: CH1

CompoundlV Compound IVa Compounds IV and We are easily dehydrohalogenated and saponifled at the same time to vitain other subsequent hydrolysis with (N 0:804

min A by first treating them with a phosphorus halide like phosphorus trichloride or tribromide and subsequently heating the dihalogen ester with alcoholic potash. To form the ester of vitamin A from Compound IV or Compound IVa, one must dehydrate by heating with p-toluene sulfonic acid in the presence of benzene, toluene or xylene.

An alternative procedure for the preparation of vitamin A consists in allowing the Grignard (Compound V), (disclosed as the Grignard of Compound VII in application Serial No. 433,226, filed March 3, 1942) to react with Compound II to form Compound VI which is partially hydrogenated (acetyleneethylene bond) to form Compound VII.

KiC CH:

OH H H Cbmpound V CH: 4 II N: O -CHr-'CH|OCR --v inether snbse uent hydro ysis with (N H0180 Compound II HaC CH: CH;

CH: B H H A g H: H C=C- =C-CEC- -CHrCHaO -R -0 Pd H CH1 Compound VI inc 0 on; O H H i H H H (I H H C=C- =C-C=C- --CHs-CH:OC-R

H LY-CH:

Compound VII To prepare vitamin A, Compound VII is dehydrohalogenated as in the case of Compound IV or Compound No, or if the ester is desired Compound VII is dehydrated with p-toluene sulfonic acid as in the case of Compound IV or Compound IV a.

A more detailed description of the various synthetic steps is to be found in the following pages:

Synthesis 0] 1-[2',6',6'-trimethyl cycloherenl'-yll-3,7-dimethyl 4,7-dihydromy 9-acetomy y'ne nonene-I (Compound III) .-A Grignard is prepared in 300 cc. of anhydrous ether from 16 of ethyl bromide and 3.6 g. of magnesium shavings. The mixture is then cooled to 0 and to it added in an atmosphere of nitrogen and with rapid stirring 20 g. of acetone carbinol 1- [2',6',6'-trimethyl cyclohexen-1-yl] -3-methyl-4-hydroxy l-ene heme-,5} in 50 cc. of anhydrous ether in the course of half an hour. The mixture is then gently refluxed for three hours, then cooled to 0 (the mixture now contains Grignard Compound I) and cc. of ethereal solution containing 9.6 g. of ,B-acetoxy ethyl methyl ketone (Compound II) is added to it in the course of one hour. The mixture, which now contains a flocculent white precipitate, is stirred and gently refluxed for 48 hours. It is then hydrolyzed by pouring the mixture on cracked ice containing 15 g. ammonium chloride. The product is extracted with ether, dried over anhydrous magnesium sulfate, the ether removed and the residue subjected to a high vacuum distillation to remove any excess acetylene carbinol and sacetoxyethylmethylketone. The residues show the following analyses; A Zerewitinofl determination showed the presence of 1.8 active hydrogen atoms as against the theoretical of 2.0. Hydrogenation (PtO-z) showed the presence of 5.3 double bonds as against the theoretical of 4.0 for Compound III. The high value obtained for hydrogenation is attributedto the hydrogenolysis, in the presence of PtOz. of the hydroxyl groups present in Compound III. Normal values are obtained when palladium black is substituted for platinum oxide.

The above procedure may be repeated with the substitution of {1-[2',6',6'-trimethyl cyclohexen- 1-yll-3-hydroxy-3-methyl l-ene heme-5} to produce Compound IIIa.

Partial hydrogenation of Compounds III and Illa to give Compounds IV and IVa.-Compounds IV and We are easily produced by dissolving Compounds III and mo in alcohol and, in the presence of palladium black, adding exactly one ll mol of gaseous hydrogen under ordinary pressures. duced by dissolving Compounds III and mo in alcohol and, in the presence of catalytically ac tive iron, hydrogenating selectively under pressures between 20 and atmospheres of hydrogen.

Conv rsion of Compounds IV and IVa. into the acetate of vitamin A.About 10 g. of Compound IV or No is dissolved in toluene containing about 0.1 g. of anhydrous p-toluene sulfonic acid and the mixture heated, in an atmosphere of nitrogen under a slightly reduced pressure, to such a temperature that the toluene together with the water formed distill over. when the toluene comes over clear, the reaction is over and the mixture is dissolved in ether and the min A.-To a solution of '7" cc. of dry benzene add" 9 g. of phosphorus trichloride and cool the mixture to 0 and, while nitrogen is passing through the solution, add slowly in the course of a half hour '75 cc. of dry benzene containing 11.22 g. of Compound IV or No. The mixture is then heated on the water bath to the boiling point of benzene for one hour, then the benzene and the excess phosphorus trichloride are removed under reduced pressure. The residue is then treated with 30 g. of potassium hydroxide in 300 cc. of alcohol, and. the resulting mixture heated on the water bath to 70-80 under slightly reduced pressure for one hour. Finally, most of the alcohol is removed under reduced pressure and the residue diluted with water to three to four times its original volume and extracted with ether. The ethereal extract is dried over anhydrous magnesium sulfate, filtered and the ether removed under reduced pressure. The residual, highly viscous, yellowish-orange oil exhibits all the properties of vitamin A. The alcoholic potash not only removes two mols of hydrogen chloride but simultaneously saponifies the acetate group thereby producing vitamin A itself.

Better yields of vitamin A are obtained by using, in the above reaction, an equivalent quantity of pyridine together with Compound IV or IVa in benzene and adding the mixture to the cold solution of benzene-phosphorus trichloride. It is also found advantageous to use phosphorus tribromide instead of phosphorus trichloride.

In all of the foregoing steps, the acetate has been used to exemplify the present process for the synthesis of vitamin A. However, the invention is not confined to this ester, since the benzoate, the propionate, the butyrate, the palmitate, or, in general, any acyloxy derivative are equally operative.

Iclaim:

1. Process which comprises mixing solutions of a compound of the formula CH: OH:

in which x stands for a halogen and one of the Y's stands for hydrogen and the other Y stands Compounds IV and We can also be pro- 101- on: in which x u a halogen and s-om- 3. Process whichcompsisesmixing ooiutions'oi pound 9! the iormuio a compound oi the iormuls in; E cm cm cm o= ne-cmo n 5 n 1: n

-C=CM inwhichitissmemberotthegroupconsisting c n of alkyl and mi groups, acidifying the resulting H cm compound uni recovering s product 01' the formula cm in which x stands for halogen. and a cm on, o oi. thetormuls. I

i H i a n n=cn- -c-c=c- -cn,-cn.o R cm H l l n o=c-cn,-cm-ocn H in which R is a. member 01' the group consisting of alkyl and aryl groups, acidifying the resulting in which one oi the 2's stands for hydrogen and compound and recovering the product of the the other for hydroxyl, and It stands for a mem- Q formula ber of the group consisting oi alkyl and aryl v on, on. 0 roups. H H 2. Process which comprises mixing solutions of H c cn, cc-c-cm-cn,ogn acornpound of the i'ormiue I I H V H oncm OH: 1 n n J: n n c=c- --cc=CMsX in which R stands for a. member. of the group i consisting of .alkyl and mi groups. I cm i 4. A compound of the formula a CH: CH:

CHI 1 p 0 in which 1: stsnds for ha en, nd a. compound 11 g=g-c--g-czc-c-onr-cmo n oi'theformuls v H 8' on. o 11 cm O=$CHr-CHr-OR a in which R is a member or the group consisting in which R stands for a. member of the group of alkyl and oryl groups, acidifying the resulting consisting of alkyl and cry! groups.

' compound and recovering the product of the 5. A compound of the formula formula. cm on.

r on, cm 0 Rec CH! H n o n -g-ci-czc-o-cnrcmo n u -c-cc-c c-c--cni-cmoa-n n a n B a H n on. K HI I i I inwhichRstandstor-amemberotthegroup in which R studs for a. oi. the group consisting or alkyl and sryi groups. consisting of slkyl and dry] groups. NICHOLAS A. MILAS. 

